Circadian feeding rhythm loss drives sex-specific β-cell dysfunction in diet-induced obesity

Diet-induced obesity (DIO), modeled by a high-fat diet (HFD), adversely affects circadian glucose homeostasis partly by dysregulating fasting/feeding cycles. However, its impact on circadian β-cell function and relevant transcriptional programs remains unclear. To investigate this, we exposed male and female C57BL/6 mice to either chow or HFD for eight weeks and assessed behavioral (feeding/activity), physiological (glucose tolerance/insulin secretion), transcriptomic (RNA sequencing (RNA-seq)), and epigenomic (Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-seq)) circadian rhythms. Additionally, we tested whether normalizing fasting/feeding cycles via time-restricted feeding (tRF) during the dark- or light-phase of the circadian cycle could mitigate DIO's deleterious effects. DIO disrupted circadian fasting/feeding rhythms, with greater disruption in males than females (p<0.05 vs. CHOW). In males, DIO abolished circadian regulation of glucose tolerance and in vivo glucose-stimulated insulin secretion (GSIS) (p<0.05 vs. chow), whereas female mice maintained circadian glucose homeostasis. RNA-seq analysis of male islets revealed a 42.1% reduction in circadian-regulated transcripts under DIO, with weakened rhythms in key β-cell pathways such as insulin secretion. Moreover, ATAC-Seq analysis indicated reduced chromatin accessibility of genes/pathways related to insulin secretion and glucose hemostasis under DIO (p<0.05 vs. chow) during both dark- or light-phase of the circadian cycle. Notably, dark-phase time-restricted feeding (tRF) restored circadian glucose tolerance, GSIS, and islet gene expression, whereas light-phase tRF enhanced β-cell function during the normally inactive/light phase of the circadian cycle, further suppressing circadian rhythmicity of the islet transcriptome. Motif analysis indicated that DIO suppressed the activity of D-box transcription factors (TFs) (DBP and TEF) while enhancing the activity of ETS family TFs (ELK1, ETS2, ELF2, and GABPA), which was partly mitigated by dark-phase tRF. Our study demonstrates that DIO disrupts circadian β-cell function and gene expression by dysregulating fasting/feeding cycles in male mice and reveals significant sex differences in how DIO affects circadian glucose homeostasis and β-cell function.